Relapse following periods of abstinence is a defining feature of drug addiction. In standard animal models of relapse, an operant response (e.g., lever press) is reinforced by drug delivery. Drug seeking is then extinguished by withholding the drug, and relapse is induced by exposure to drugs, drug-cues/contexts, or stress. Drug and non-drug reinforcers are known to interact in the control of behavior, and availability of alternative non-drug reinforcers decreases drug taking. Behavioral interventions arranging non-drug reinforcers have been very successful, but when such treatment ends, the discontinuation of alternative reinforcement is often associated with relapse. In addition, some potentially stress-related sources of relapse (e.g., changes in familial or vocational circumstances) might be characterized as involving the loss of alternative non-drug reinforcers. Standard animal models of relapse do not examine such relapse induced by loss of alternative non-drug reinforcement. Our laboratory has developed the resurgence model in which extinguished drug seeking increases (i.e., relapses) when an alternative source of non- drug reinforcement is subsequently removed. However, a long-standing criticism of animal models of relapse, including the resurgence paradigm, is that they achieve suppression of drug seeking by extinguishing drug seeking prior to relapse testing. The concern with the use of extinction is that cessation of drug seeking by humans is clearly not the result of extinction of drug seeking. Instead, considerable evidence suggests that the experience of negative consequences as a result of drug use is a contributing factor. The goal of this R21 Exploratory/Developmental grant is to develop a version of the resurgence model to examine relapse induced by loss of alternative reinforcement following suppression of cocaine seeking with negative consequences, rather than extinction. The project addresses a long-standing barrier to progress in the field resulting from the use of extinction as the means to suppress drug- seeking prior to relapse. By developing a version of the resurgence procedure using negative consequences to suppress drug seeking, the proposed research could result in a more appropriate model for examining the behavioral and neurobiological mechanisms of relapse induced by loss of non-drug reinforcement.